Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation
Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation
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DOI：
10.1053/j.gastro.2007.06.016
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发表时间：
2007-09-01
期刊：
影响因子：
29.4
通讯作者：
Taniguchi, Hideki
中科院分区：
文献类型：
--
作者：
Chiba, Tetsuhiro;Zheng, Yun-Wen;Taniguchi, Hideki
背景和目标：具有增强的或获得的自我更新能力的转化的造血干细胞/祖细胞作为白血病干细胞发挥功能。在多种实体癌中，干/祖细胞也可能是致癌作用的靶点。然而，目前尚不清楚干细胞功能的破坏是否直接导致癌症的发生。我们试图阐明肝干/祖细胞自我更新的机制以及干细胞功能与肝癌发生的关系。研究方法：使用逆转录病毒或慢病毒介导的基因转移，在c-Kit-CD 29（+）CD 49 f（+）/（低）CD 45-Ter- 119-肝干/祖细胞中进行了多梳组蛋白Bmil和Wnt/β-连环蛋白（负责许多类型干细胞自我更新能力的分子）的功能分析。还通过移植到非肥胖糖尿病/严重联合免疫缺陷小鼠中来评估用所示逆转录病毒转导的这些细胞的致瘤性。结果：Bmil和组成型激活的β-catenin突变体的强制表达同样促进肝干/祖细胞的自我更新。Bmi 1-或P-catenin-转导的细胞从单个肝干/祖细胞克隆扩增的移植产生肿瘤，其表现出肝细胞癌和胆管癌的组合的组织学特征。结论：这些观察结果表明，肝干细胞/祖细胞的自我更新失调是肝癌发生的早期事件，并且它们突出了Bmil和Wnt/β-连环蛋白通路在调节肝脏中正常或癌症干细胞的自我更新中的重要作用。
Background& Aims: Transformed hematopoietic stem/progenitor cells with an enhanced or acquired self-renewal capability function as leukemic stem cells. In a variety of solid cancers, stem/progenitor cells could be also targets of carcinogenesis. However, it remains unclear whether disruption of stem cell function directly contributes to cancer initiation. We sought to elucidate the mechanisms of selfrenewal in hepatic stem/progenitor cells and the relation between stem cell function and hepatocarcinogenesis. Methods: Functional analyses of polycomb-group protein Bmil and Wnt/beta-catenin, the molecules that are responsible for the self-renewal capability of many types of stem cells, were conducted in c-Kit- CD29(+) CD49f(+)/(low)CD45 -Ter- 119- hepatic stem/ progenitor cells using retrovirus- or lentivirus-mediated gene transfer. The tumorigenicity of these cells transduced with the indicated retroviruses was also assessed by transplantation into nonobese diabetic/ severe combined immunodeficient mice. Results: Forced expression of Bmil and constitutively active beta-catenin mutant similarly promoted the self-renewal of hepatic stem/progenitor cells. The transplantation of Bmi1- or P-catenin-transduced cells clonally expanded froiii single hepatic stem/progenitor cells produced tumors, which exhibited the histologic features of combined hepatocellular and cholangiocarcinoma. Conclusions: These observations imply that the dysregulated self-renewal of hepatic stem/progenitor cells serves as an early event in hepatocarcinogenesis, and they highlight the important roles of Bmil and the Wnt/beta-catenin pathway in regulating the seff-renewal of normal or cancer stem cells in liver.